A Novel Y-Shaped, S-O-N-O-S-Bridged Crosslink between Three Residues C22, C44, and K61 Is a Redox Switch of the SARS-CoV-2 Main Protease

Yang, K. S.; Kuo, S.-T. A.; Blankenship, L. R.; Sheng, Y. J.; Sankaran, B.; Li, P.; Fierkee, C. A.; Russell, D. H.; Yan, X.; Xu, S.; Liu, W. R.

doi:10.1101/2022.04.29.490044

bioRxiv · 10.1101/2022.04.29.490044

A Novel Y-Shaped, S-O-N-O-S-Bridged Crosslink between Three Residues C22, C44, and K61 Is a Redox Switch of the SARS-CoV-2 Main Protease

Yang, K. S.·Kuo, S.-T. A.·Blankenship, L. R.·Sheng, Y. J.·Sankaran, B.·Li, P.·Fierkee, C. A.·Russell, D. H.·Yan, X.·Xu, S.·Liu, W. R.

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Abstract

As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (MPro) for pathogenesis and replication. During the crystallographic analyses of MPro crystals that were exposed to the air, a uniquely Y-shaped, S-O-N-O-S-bridged posttranslational crosslink that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel posttranslational modification, this crosslink serves as a redox switch to regulate the catalytic activity of MPro, a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more opened active site that can be potentially targeted for the development of novel SARS-CoV-2 antivirals. The inactivation of MPro by this crosslink indicates that small molecules that lock MPro in the crosslinked form can be potentially used with other active site-targeting molecules such as paxlovid for synergistic effects in inhibiting the SARS-CoV-2 viral replication. Therefore, this new finding reveals a unique aspect of the SARS-CoV-2 pathogenesis and is potentially paradigm-shifting in our current understanding of the function of MPro and the development of its inhibitors as COVID-19 antivirals.

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Yang, K. S., Kuo, S.-T. A., Blankenship, L. R., Sheng, Y. J., Sankaran, B., Li, P., Fierkee, C. A., Russell, D. H., Yan, X., Xu, S., Liu, W. R.. 2022-04-29. A Novel Y-Shaped, S-O-N-O-S-Bridged Crosslink between Three Residues C22, C44, and K61 Is a Redox Switch of the SARS-CoV-2 Main Protease. https://doi.org/10.1101/2022.04.29.490044

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